When scientists first began looking at drugs derived from opium ("opiates"),
they were interested in identifying drugs that would be good painkillers,
but would not lead to patients' becoming addicted to the drug -- a problem
with codeine and morphine.

In 1929, Dr. Lyndon F. Small established the Drug Addiction Laboratory,
the ancestor of today's LMC. Seeking to create painkillers which
would not cause addiction, Small studied and modified the morphine
molecule and related opium products. This work was based on the assumption
that the drug's effects were directly related to its molecular structure.
Small's assumption proved correct. Metopon, a potent opiate painkiller,
was among his most notable contributions. With metopon, partial separation
of the painkilling effects from the undesired addictive property
was at last achieved. This finding was the underpinning of much research
that continues today into a total separation of painkilling and addictive
effects.

Dr. Nathan Eddy evaluated Small's compounds for their painkilling effectiveness
and potential to be addictive, and Dr. Clifton Himmelsbach conducted the
first clinical tests with these drugs in human subjects. Early studies
on metopon showed it produced a less severe addiction than morphine and
other opiates. This finding encouraged scientists to hope that the addictive
side effect could be further separated from the painkilling action.

Dr. Everette May and Dr. Eddy worked to develop opiates that relieved
pain without the potential for abuse and to discover synthetic substitutes
for opiates--called opioids. Based on May's work on benzomorphans, the
drug pentazocine was introduced in the 1960s. Pentazocine was the first
drug used in clinical practice as a painkiller which combined the pain-relieving
effects of morphine with the effects of opiate antidote. Such drugs are
called mixed agonists-antagonists because they produce some opiate effects
while blocking the opiate effects of other drugs. But pentazocine was not
as effective as morphine for severe pain, and produced hallucinations at
higher doses.

The drug buprenorphine was developed using the agonist-antagonist construct.
It is a promising drug for the detoxification of heroin addicts because
it produces less intensive withdrawal symptoms, is relatively non-toxic,
and can be used by outpatients. It is also being studied as a therapy for
individuals dependent on cocaine.

Dr. Small prepared hundreds of potential opiate drugs for pharmacological
evaluation, keeping them in cigar boxes. Small's samples have been
used by many investigators to identify opiate products.

Public Health Service physician Clifton K. Himmelsbach

Medicinal chemist Everette May and pharmacologist Nathan B. Eddy

The bottom shows that metopan (methyldihydromorphinone) fails to block
morphine withdrawal symptoms completely (center) and that its own
withdrawal syndrome is milder than that produced by morphine (right).